WO2007063946A1 - Diagnostic et remede pour une maladie provoquee par l’aggregation et/ou le depot d’amyloide - Google Patents

Diagnostic et remede pour une maladie provoquee par l’aggregation et/ou le depot d’amyloide Download PDF

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WO2007063946A1
WO2007063946A1 PCT/JP2006/323955 JP2006323955W WO2007063946A1 WO 2007063946 A1 WO2007063946 A1 WO 2007063946A1 JP 2006323955 W JP2006323955 W JP 2006323955W WO 2007063946 A1 WO2007063946 A1 WO 2007063946A1
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group
amyloid
compound
transition metal
salt
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PCT/JP2006/323955
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English (en)
Japanese (ja)
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Kazunori Bando
Kazumi Taguchi
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Fujifilm Ri Pharma Co., Ltd.
Daiichi Sankyo Company, Limited
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Application filed by Fujifilm Ri Pharma Co., Ltd., Daiichi Sankyo Company, Limited filed Critical Fujifilm Ri Pharma Co., Ltd.
Priority to EP06833758.3A priority Critical patent/EP1956013B1/fr
Priority to JP2007548001A priority patent/JP4738419B2/ja
Priority to US12/095,320 priority patent/US8022075B2/en
Publication of WO2007063946A1 publication Critical patent/WO2007063946A1/fr

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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/18—Benzimidazoles; Hydrogenated benzimidazoles with aryl radicals directly attached in position 2
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    • C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
    • C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
    • C07D263/56—Benzoxazoles; Hydrogenated benzoxazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
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    • C07D277/62—Benzothiazoles
    • C07D277/64—Benzothiazoles with only hydrocarbon or substituted hydrocarbon radicals attached in position 2
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    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
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    • G01N2333/46—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans from vertebrates
    • G01N2333/47—Assays involving proteins of known structure or function as defined in the subgroups
    • G01N2333/4701—Details
    • G01N2333/4709—Amyloid plaque core protein
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2500/00—Screening for compounds of potential therapeutic value
    • G01N2500/04—Screening involving studying the effect of compounds C directly on molecule A (e.g. C are potential ligands for a receptor A, or potential substrates for an enzyme A)

Definitions

  • the present invention relates to a diagnostic and therapeutic agent for diseases caused by amyloid aggregation and Z or deposition.
  • Amyloid is a unique protein having a fibrous structure, and is hematoxylin and eosin-stained. In alkaline Congo red staining, it dyes orange-red, and when viewed with a polarizing microscope, it exhibits green birefringence. In electron microscopes, unbranched fiber forces with a width of 7-15 nm are also possible. It is said that there are at least 20 proteins that make up the force amyloid that looks the same morphologically. Monomer is not toxic and is considered to cause organ damage when sputum aggregates. . A common feature of this protein aggregate is that it is rich in ⁇ -sheet structure and is hardly soluble.
  • Amyloidosis is a group of diseases that cause dysfunction by amyloid fibrils being deposited or accumulated outside the cells of various organs throughout the body. According to the new classification of the Ministry of Health, Labor and Welfare's Specified Disease Research Group, amyloidosis is divided into systemic and local as follows.
  • Amyloid derived from immunoglobulin (from light chain chain, kappa chain and heavy chain) is deposited in systemic organs.
  • amyloid derived from serum amyloid A SAA
  • an acute phase protein is deposited.
  • Familial amyloid poly-Eurobachi-I (classified as type I IV) presents with a unique sensory impairment 'motor impairment-Eurobachi-I and autonomic neuropathy (atypical transthyretin). Other Include familial Mediterranean fever and Muckle-Wells syndrome.
  • Wild-type transthyretin accumulates not only in the heart but also in the lungs and blood vessel walls of the digestive tract.
  • Amyloid associated with medullary thyroid cancer Type 2 diabetes' insulinoma, localized atrial amyloidosis
  • Diagnosis of systemic amyloidosis is variable because amyloid accumulates in any organ of the body. Initially, nonspecific initial symptoms such as general malaise, weight loss, edema, anemia, etc. begin, congestive heart failure, nephrotic syndrome, malabsorption syndrome, peripheral neuropathy, orthostatic hypotension, hand Symptoms such as root canal syndrome and enlarged liver are known. As a clinical test, amyloid constituent proteins are detected by hematological serology. In addition, “ m Tc-pyrophosphate scintigraphy is effective for the detection of cardiac amyloid,” however, “ m Tc-pyrophosphate is not specific because it also accumulates in ischemic sites.
  • amyloidosis For the definitive diagnosis of amyloidosis, there is a need to prove the amyloid deposition by collecting tissue by biopsy of organ force suspected of amyloid deposition. After pathological examination by biopsy, immunohistological examination, serological examination, and genetic examination are combined to identify amyloid precursor protein and lead to definitive diagnosis. In order to diagnose amyloidosis, it is essential to select a tissue that accumulates a large amount of amyloid and biopsy from that site. It becomes.
  • Reactive AA amyloidosis is a disease in which amyloid derived from the acute phase reactive protein Serum Amyloid A (SAA) is deposited, secondary to chronic inflammatory diseases.
  • SAA Serum Amyloid A
  • rheumatoid arthritis which has a prevalence of 0.3-0.8% per population in Japan, is also a primary disease of AA amyloidosis, and about 10% of the complications are observed.
  • This amyloid accumulation is a disease that causes various organ damages by depositing extracellularly in tissues and is a complication with a very poor prognosis.
  • the 50% survival rate is 2 to 4 years. In general, diagnosis can only be done by confirming that amyloid has accumulated by biopsy.
  • SAP serum amyloid component
  • BBB blood-brain barrier
  • Alzheimer's disease is a disease that is becoming a serious social problem with localized amyloidosis.
  • Japan the number of patients with dementia is increasing rapidly with the aging of the population, and the treatment and care of dementia is an issue that must be solved urgently in terms of medical economics.
  • it is estimated that there will be 3 million people with dementia, many of whom are allegedly suffering from Alzheimer's disease.
  • Alzheimer's disease patients There are currently 4 million Alzheimer's disease patients in the United States, and an estimated 1 million in Japan.
  • Alzheimer's disease is a disease with a poor prognosis in which half of the patients die within 3 to 8 years from the onset of disease, and the disease progresses with certainty.
  • Image diagnosis is an important test for differentiating Alzheimer's disease from other diseases.
  • evidence from contrast between autopsy and images is not available.
  • PET and SPECT which measure changes in glucose metabolism and cerebral blood flow
  • CER AD Consortium to Establish a registry for Alzneimer s Disease, Braak et al., etc.
  • CERAD's pathological diagnosis criteria semi-quantitatively determine the number of typical senile plaques stained with silver stain, the most intense of Alzheimer's lesions. Compared with the number of senile plaques classified as sparse, 6 / mm moderate, 35 / mm frequent and standardized by age group for neocortex, it is evaluated as definite, probable, normal .
  • a novel amyloid imaging agent having a thioflavin structure was developed at the University of Pittsburgh and called Pittsburgh Compound-BC-PIB) (Patent Documents 3 and 4). It has been reported that when C—PIB is administered to mildAD patients, amyloid accumulates and shows significant retention compared to controls in the cortical region, clearly distinguishing between Alcino-Ima disease and normal subjects. Yes. However, since 11 C-PIB retention is only doubled in the AD patient group, a diagnostic agent that can provide higher contrast is desired to examine the degree of amyloid accumulation in more detail. This is an essential condition for determining whether a patient with symptoms such as mild cognitive impairment (MCI), which is more difficult to diagnose, progresses to Arnno-ima.
  • MCI mild cognitive impairment
  • 11 C PIB was administered to mice overexpressing APP to generate amyloid aggregates (PSI ZAPP mice) and examined by animal PET scanner. As a result, there was a difference in retention time between PSlZAPP mice and normal mice. Is not seen. In vivo animal experiments indicate that PIB is unable to image amyloid accumulation in PSlZAPP mice due to its low affinity for amyloid aggregates. Furthermore, “C-PIB labeled nuclide 11 C has a half-life of 20 minutes. Thus, the positron-emitting nuclide used in imaging generally has a very short half-life, and the radionuclide is a cyclotron.
  • a commercially available and industrially useful method is a nuclide-labeled formulation with a longer half-life (about 6-72 hours) that emits y-rays.
  • the nuclide along this purpose, there are 123 iota and 9 9m Tc.
  • 123 1 studied 123 I- IMPY labeling purposes is reported from Pennsylvania University (Patent Document 5), have a high affinity for amyloid in AD patients brain and Tg mice.
  • An amyloid-binding probe with a thioflavine skeleton labeled with a radioisotope has an N-alkylamine structure.
  • N-alkylamine structure is biological It is common to undergo internal metabolism.
  • Non-Patent Document 2 radioligand metabolites that have lost amyloid-binding properties and have undergone N-dealkylation while maintaining lipid solubility pass through the blood-brain barrier and enter the brain, thereby being related to amyloid. No accumulation (Non-Patent Document 2). Therefore, the development of derivatives whose metabolites are not detected in the brain is strongly desired.
  • amyloidosis disease substances that inhibit aggregation and Z or deposition of amyloid (including amyloid protein and amyloid-like protein) are considered to be effective. Furthermore, in the case of amyloidosis of the brain typified by Aruno-Ima disease, it is required to be a diagnostic or therapeutic agent that crosses the blood-brain barrier.
  • Patent Document 1 WO2005Z042461 pamphlet
  • Patent Document 2 Japanese Translation of Special Publication 2002-523383
  • Patent Document 3 WO 2004Z083195 pamphlet
  • Patent Document 4 Japanese Translation of Special Publication 2004-506723
  • Patent Document 5 Special Table 2005—512945
  • Non-Patent Document 1 Hawkins PN, Lavender JP, Pepys MB., N Engl J Med. 1990 Aug 23; 323 (8): 508-13.
  • Non-Patent Document 2 Kung MP, Hou C, Zhuang ZP, Cross AJ, Maier DL, Kung HF., Eur J Nucl Med Mol Imaging. 2004 Aug; 31 (8): 1136-45. Epub 2004 Mar 9.
  • the present invention relates to a diagnostic agent that specifically binds to amyloid aggregates and Z or deposits, and can image and quantify diseases caused by amyloid aggregation and Z or deposits.
  • the purpose is to provide.
  • Another object of the present invention is to inhibit amyloid aggregation and Z or deposition, and provide a preventive and Z or therapeutic agent for diseases caused by these.
  • an object of the present invention is to provide a method for preventing a disease caused by aggregation and Z or deposition of amyloid and screening for a Z or therapeutic agent.
  • the present inventors searched for a substance that specifically binds to amyloid, passes through the blood-brain barrier, and no metabolite is detected in the brain, and is represented by the following general formula (1).
  • the present invention has been completed by finding that the compound has potent properties and is useful as a diagnostic agent and a preventive and z- or therapeutic agent for diseases caused by amyloid aggregation and Z or deposition.
  • the present invention relates to the general formula (1)
  • X 1 represents a bicyclic heterocyclic group which may have a substituent
  • X 2 represents a hydrogen atom, a halogen atom or a chelate-forming group
  • the ring containing A represents a benzene ring or a pyridine ring
  • the ring containing B represents a 5-membered aromatic heterocyclic group which may have a substituent, and this ring is bonded to a benzene ring or a pyridine ring in the formula at a carbon atom.
  • the present invention also provides a diagnostic, prophylactic and Z or therapeutic pharmaceutical comprising the compound represented by the general formula (1), a salt thereof, a solvate thereof, or a transition metal coordination body thereof. Is to provide.
  • the present invention also provides use of the compound represented by the above general formula (1), a salt thereof, a solvate thereof or a transition metal coordination body thereof for the production of a medicine.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound represented by the above general formula (1), a salt thereof, a solvate thereof or a transition metal coordination body thereof, and a pharmaceutically acceptable carrier. To do.
  • the present invention relates to amyloid aggregation and administration characterized by administering an effective amount of a compound represented by the general formula (1), a salt thereof, a solvate thereof, or a transition metal coordination body thereof.
  • a method for preventing and / or treating a disease caused by deposition is provided.
  • the present invention provides administration of a detectable amount of a compound represented by the above general formula (1), a salt thereof, a solvate thereof, or a transition metal coordination compound thereof, and the labeled compound is amyloid.
  • the present invention provides a method for imaging amyloid deposits characterized in that it takes a sufficient time to bind to the deposits and detects a labeled compound bound to the amyloid deposits.
  • the present invention is a production intermediate of the compound of the general formula (1), the general formula (2)
  • R 1 represents an oxygen atom, a sulfur atom or NR 3 (R 3 represents a hydrogen atom, a hydroxy group or an alkoxy group);
  • R 2 may have a substituent, may be an alkyl group, a substituent! /, May! /, A alkenyl group, or an amino group which may have a substituent. Show;
  • the ring containing X 1 , X 2 and A is the same as described above. )
  • the present invention relates to a binding property between an analyte and amyloid using the compound represented by the general formula (1), a salt thereof, a solvate thereof, or a transition metal coordination body thereof. Detecting and measuring amyloid aggregation and the degree of Z or deposition, which is characterized by the prevention or treatment of diseases caused by aggregation or deposition of amyloid, and screening using such screening methods The present invention provides a preventive and Z or therapeutic agent for diseases caused by aggregation and Z or deposition of amyloid containing a selected substance.
  • the compound (1) of the present invention has high affinity for amyloid aggregates or deposits and passes through the blood-brain barrier. In addition, there should be no metabolites in the brain, which is highly stable in vivo. Therefore, safety is high. Therefore, the compound (1) of the present invention is useful as a diagnostic agent for a disease caused by amyloid aggregation and Z or deposition, particularly as a diagnostic imaging agent.
  • the compound (1) of the present invention has an action of inhibiting amyloid aggregation and Z or deposition, a drug caused by amyloid aggregation and Z or deposition, that is, a prophylactic and Z or therapeutic agent for amyloidosis Useful as.
  • the compound (1) of the present invention is useful for the prevention of diseases caused by aggregation and Z or deposition of amyloid and the screening of Z or therapeutic agents.
  • FIG. 1 is a diagram showing a correlation equation between logkw and log D7.4 of a fat-soluble standard substance.
  • FIG. 2 A graph showing the relationship between the amount of amyloid
  • FIG. 3 is a diagram showing CD spectra of amyloid
  • FIG. 4 is a graph showing a comparison between the amount of ⁇ -sheet of amyloid
  • FIG. 5 is a diagram showing the results of analysis of radioactive substances in the brain after administration to rats.
  • FIG. 6 shows the results of in vitro specific binding experiments using Alzheimer's disease brains. BEST MODE FOR CARRYING OUT THE INVENTION
  • X 1 represents a bicyclic heterocyclic group which may have a substituent.
  • Bicyclic heterocyclic groups include 5-membered 5-membered bicyclic heterocyclic groups, 6-membered 5-membered heterocyclic groups, 6-membered 6-membered heterocyclic groups, etc. However, a 6-membered ring and a 5-membered heterocyclic group are preferable.
  • a bicyclic heterocyclic group a 6-membered 5-membered heterocyclic group containing 2 to 4 heteroatoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom is a preferable example.
  • bicyclic groups which can replace the heterocyclic group represented by X 1, a halogen atom, a hydroxyl group, alkyl group, alkyl tin group, halogenoalkyl group, halogenoalkylcarboxylate - Rua amino group and the chelating group There are 1 to 3 that can be selected.
  • halogen atom examples include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
  • an alkyl group a C1-C8 alkyl group is mentioned, Preferably it is a C1-C6 alkyl group.
  • the alkyl group may be linear or branched. Specific examples include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a tert-butyl group, and a pentyl group.
  • the alkyl tin group examples include a tri (C—C alkyl) tin group, and a tri (C—C alkyl) tin group is preferable.
  • Halogenoalkyl groups include phenoxy, oral C 1 -C alkyl groups, especially halogeno C—C
  • a 1 8 1 6 alkyl group is preferred. Specific examples include a chloromethyl group, a bromomethyl group, a fluoromethyl group, a odomethyl group, a chloroethyl group, a bromoethyl group, a fluorethyl group, a chloroethyl group, a chloropropyl group, a fluorpropyl group, and a chloropropyl group.
  • the halogenoalkylcarbolumino group includes a halogeno (C—C alkyl) carbole group.
  • amino group preferably a halogeno (C-C alkyl) carbo-amino group.
  • chlorobutanoylamino group, fluorobutanoylamino group, pseudobutanoylamino group and the like chloroacetamino group, a fluoroacetamino group, a odoacetamino group, a chloropropanoylamino group, a fluoropropanoylamino group, and a chloropropanoylamino group.
  • Examples of the chelate-forming group include the following groups.
  • the formula is described as a form including a chelate-form transition metal atom.
  • M represents a transition metal atom such as Ga, Tc, Re, In, etc.
  • halogen atom and the chelate-forming group represented by [0033] X 2 may be the same as those exemplified as a substituent on the heterocyclic Shikimoto two rings of the X 1.
  • the ring containing A is a benzene ring or a pyridine ring.
  • the benzene ring any of o-phenylene group, m-phenylene group, and p-phenylene group may be used.
  • a pyridine ring if the substitution position of X 1 is 1, any of 2-pyridyl, 3-pyridyl, and 4-pyridyl may be used. Yes.
  • the ring containing B is bonded to the benzene ring or pyridine ring in the formula with a carbon atom.
  • the 5-membered aromatic heterocyclic group represented by the ring containing B include a 5-membered aromatic heterocyclic group having 1 to 4 heteroatoms selected from a nitrogen atom, an oxygen atom, and a sulfur atomic energy. Further, a 5-membered aromatic heterocyclic group having 2 to 4 heteroatoms, particularly a nitrogen-containing 5-membered aromatic heterocyclic group is preferred.
  • oxazolyl group examples include oxazolyl group, isoxazolyl group, thiazolyl group, isothiazolyl group, pyrazolyl group, imidazolyl group, triazolyl group, thiadiazolyl group, oxadiazolyl group, tetrazolyl group and the like.
  • Examples of the group that can be substituted on the ring containing B include a halogen atom, an alkyl group, an alkoxy group, a chelate-forming group, and the like.
  • Examples of the halogen atom, alkyl group, and chelate-forming group include those exemplified as the substituent on the bicyclic heterocycle of X 1 .
  • an alkoxy group a C1-C8 alkoxy group is mentioned, Preferably it is a 1-6 alkoxy group.
  • Specific examples of the alkoxy group may be linear or branched and include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, and tert-butoxy.
  • the ring containing X 1 , X 2 , or B has at least one halogen atom.
  • the compound (1) of the present invention is labeled with a radionuclide. It is desirable to use Radioisotopes utilized for the purposes of the present invention include nuclides that emit 8) rays, gamma rays, positron radiation, and x-rays.
  • the radioactive element that may be used to label the compound (1) of the present invention, 3 H, 14 C, C , 13 N, 15 0, 18 F, 35 S, 62 Cu, 64 Cu, 6 7 Ga ⁇ 68 Ga ⁇ "mTc ⁇ i In, 122 I, 123 I, 124 I, 125 I, 131 I, 133 Xe, 201 T1 etc. 3 H, 14 C, 35 S, 131 I can be mentioned in vitro. It is a frequently used nuclide.
  • nuclides that emit gamma rays or positron emitting nuclides with high in vivo permeability are used.
  • An amyloid can be imaged by labeling the compound (1) of the present invention and administering it in vivo. This method is non-invasive with very little damage to the patient.
  • Positron Yang “Electron” means an electron having a positive charge. Positively charged positrons and negatively charged ordinary electrons have the property of attracting each other, and positrons immediately combine with electrons.
  • a PET (Positron Emission Tomography) image excellent in resolution and quantification can be obtained by simultaneously measuring them with a pair of detectors.
  • Nuclides to be used for this purpose is 11 C, 13 N, 15 0 , 18 F include, in particular, 11 C and 18 F are preferred.
  • positron-emitting nuclides used in imaging generally have a very short half-life, and since radionuclides are produced with a cyclotron, the compounds are labeled. Therefore, it is necessary to control the quality of the labeled compound, and it is possible to label with positron emitting nuclides in Japan and visualize amyloid in the living body. Facilities are limited.
  • 68 Ga is a metal radionuclide and a chelate site must be introduced into the compound in order to bind to the compound.
  • Typical examples of the 68 Ga-chelate structure that can be introduced are the above formulas (A) and (B) (in this case, M in the formulas (A) and (B) is Ga).
  • the nuclide generally used to produce commercially useful images is a method of labeling drugs with nuclides that emit gamma rays.
  • the detector detects the gamma rays emitted by the compound force and images them as two dimensions. This is accomplished by attaching a collimator to detect only gamma rays from a specific direction and obtaining positional information along with the detection of gamma rays.
  • SPECT single photon emission computed tomography
  • SPECT detects relatively low energy and gamma rays compared to PET, so the influence of absorption and scattering rays is large. Therefore, the power that is considered to be inferior to PET in terms of quantitativeness. It has become possible to perform quantitative analysis in SPECT.
  • gamma emitting nuclides used in the SPECT 67 Ga, 99m Tc, i In, 123 I, 124 I, I, 133 Xe, 201 T1 , etc.
  • 99m Tc is a radionuclide that is readily available from the 99 Mo- 99m Tc generator and is very suitable for routine inspection.
  • Tc is a metal radionuclide and a chelate site must be introduced into the compound to bind to the compound.
  • a typical example of a 99 M Tc-chelate structure that can be introduced is the above formula ( ⁇ (wherein M in the formulas (C) to (J) is Tc).)
  • MRI magnetic resonance imaging
  • MRS spectroscopy
  • EPR electron paramagnetic resonance
  • Examples of the salt of the compound of the present invention include salts of inorganic acids and organic acids.
  • Examples of inorganic acid salts include salts with hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid and the like.
  • organic salts include maleic acid, fumaric acid, benzoic acid, ascorbic acid, succinic acid, oxalic acid, bismethylenesalicylic acid, methanesulfonic acid, ethanedisulfonic acid, acetic acid, propionic acid, tartaric acid, salicylic acid, citrate, Darconic acid, Lactic acid, Malic acid, Mandelic acid, Keihic acid, Citraconic acid, Aspartic acid, Stearic acid, Palmitic acid, Itaconic acid, Glycolic acid, ⁇ -Aminobenzoic acid, Glutamic acid, Benzenesulfonic acid, Theophosphoric acid, 8 -Salts with 8-halotheophylline such as bromo-theophylline.
  • the solvate of the compound of the present invention include hydrates and various organic solvates.
  • the present invention process for the preparation of compound (1) is a phase differences by the structure of the ring containing heterocyclic group and B of X 1, ring containing force or B to form a heterocyclic ring of X 1 to the end It can be roughly divided into two kinds of manufacturing methods depending on the last formation.
  • the ring containing A and the ring containing B are not limited to the heterocycles described in the reaction formula.
  • an aldehyde form (2-a) is obtained, and by reacting this with a methyl isocyanide, an oxazole form (1-a) is obtained.
  • the reduction reaction of the nitrile is carried out, for example, by using a reducing agent such as dialkylaluminum hydride such as diisobutylaluminum hydride, catecholallan, Raney nickel, or stannous chloride.
  • the reaction is carried out at a temperature of 10 ° C. to 50 ° C. in an ether type solvent such as a halogenated hydrocarbon such as dichloromethane or tetrahydrofuran.
  • Examples of the methylisocyanides used for the conversion of the aldehyde (2-a) force to the oxazole (1-a) include p-toluenesulfonylmethyl isocyanide, benzotriazolylmethyl isocyanide and the like.
  • the reaction is carried out by heating in an alcohol solvent such as methanol for 5 to 24 hours in the presence of a base such as potassium carbonate, sodium hydrogen carbonate or sodium hydroxide.
  • the thioamide form (2-b) is obtained by reacting the nitrile form (3) with thioacetamide, and the thiazole form (1b) is obtained by reacting this with a halogenoacetaldehyde.
  • the reaction of nitrile (3) with thioacetamide is carried out in polar solvents such as dimethylformamide, dimethylacetamide, N-methylpyrrolidone in the presence of acids such as hydrochloric acid and sulfuric acid. This is done by heating.
  • halogenoacetaldehyde used for the conversion to thiazole (1-b)
  • halogenoacetaldehyde include chloroacetaldehyde, bromoacetaldehyde, bromoacetaldehyde decetylacetal and the like.
  • the reaction is carried out by heating in the presence of a base such as triethylamine or pyridine.
  • the tetrazole body (1c) By reacting the nitrile body (3) with an azide compound to cyclize, the tetrazole body (1c) is obtained.
  • the azide compound used include azidotrimethylsilane and azinatrium.
  • the reaction is preferably carried out under heating in the presence of a metal catalyst such as trimethylaluminum.
  • the compound (2-d) is obtained by reacting the aldehyde compound (2-a) with a Grignard reagent such as methylmagnesium bromide and then water to obtain the compound.
  • the body (2-e) is obtained.
  • the acetofenone form (2-e) is reacted with dimethylformamide acetal to obtain a compound (2-f), which is reacted with hydrazine to obtain a violazole form (1 e ). Further, when hydroxylamine is reacted with compound (2-f), isoxazole compound (1-f) is obtained.
  • the oxidation reaction of the alcohol (2-d) can be carried out using manganese dioxide, chromium trioxide, metabenzoic perbenzoic acid, dimethyl sulfoxide or the like.
  • Reaction of the acetophenone (2-e) and dimethylacetamide acetal is carried out by heating to 130-160 ° C.
  • the ring closure reaction of compound (2-f) with hydrazine is carried out by heating in an alcohol solvent such as ethanol.
  • the ring closure reaction of compound (2-f) with hydroxylamine is carried out by heating in an alcohol solvent such as ethanol.
  • Compound (2e) is reacted with a halogenating agent to obtain compound (2g), and formamide is reacted therewith to obtain an imidazole form (l-g).
  • a halogenating agent N-halogeno succinimide, tetraptyl ammotribromide, bromine and the like are used.
  • the reaction between compound (2-g) and formamide is carried out under heating conditions.
  • the compound (1) of the present invention can be produced, for example, according to the following reaction formula.
  • R 1 represents a hydrogen atom or the same substituent as the substituent on the heterocyclic group of X 1
  • Y represents a carbon atom or a nitrogen atom
  • X 4 represents a halogen atom.
  • X 2 , the ring containing A and the ring containing B are the same as above
  • Compound (1-h) is obtained by reacting aromatic amine (4) with compound (5). This reaction is usually carried out in a solvent in the presence of a base at room temperature or under heating, but depending on the type of compound (5), it can be produced in a high yield by carrying out the reaction under heating and reflux. Can do.
  • the base that can be used in this reaction include inorganic bases such as potassium carbonate and sodium hydrogen carbonate, and organic bases such as triethylamine.
  • an organic solvent that does not react with a substrate, a product, a reagent, or the like for example, various solvents such as ethanol, methanol, ether, tetrahydrofuran, acetone, benzene, and toluene can be used.
  • solvents such as ethanol, methanol, and acetone.
  • the compound represented by the general formula (2) is useful as an intermediate for producing the compound (1) of the present invention.
  • the aldehyde (2-a), the compound (5), and the compound (7) used in the above reaction are known compounds, or the formation reaction of the X 1 heterocycle, or B It can be produced according to the reaction of forming a ring containing it.
  • promoacetophenone compound (5) can be produced from casee phenone compound by a known method (Synthesis. 1976, 194, 196; Org. Synth, 194 3, I, 127). Can do.
  • the method for producing a benzothiazole structure and a benzoxazole structure can be produced by reacting an aldehyde compound with an Arin compound. Usually, the reaction is carried out in a solvent, and it is produced at room temperature or under heating. Dimethyl sulfoxide or the like can be used as a solvent, and the reaction is preferably performed at about 160 ° C! /.
  • Substituents on the ring containing X 1 , X 2 and B can be converted by various conversion methods by conventional methods.
  • a trialkyltin group can be obtained by reacting a halogen compound with trialkyltin in the presence of a catalyst such as tetra (triphenylphosphine) palladium.
  • a catalyst such as tetra (triphenylphosphine) palladium.
  • the conversion from trialkyltin group to iodine body may be achieved by reacting iodine.
  • the compound (1) of the present invention produced by the above method can be isolated and purified as a free form or a salt thereof. Isolation and purification can be performed by applying known chemical operations such as extraction, recrystallization, and various chromatography.
  • a C11 labeled body which is a compound for PET, can be obtained, for example, as follows.
  • C] CO obtained from cyclotron is used as a raw material.
  • Methyl iodide reaction using C] methyl iodide and [ nc ] methyl triflate is used.
  • a C-11 labeled product can be obtained.
  • a C-11 labeled product can be obtained by a coupling reaction with an organic tin compound using Pd as a catalyst. Examples of labeling schemes by each method are shown below.
  • R 2 SnMe 3 , SnBu 3
  • the F-18 labeling method includes the F method, which is an electrophilic substitution reaction, and the acetyl hypofluorite method.
  • the second method uses [ 18 F] F containing a carrier as the raw material, so the specific activity tends to decrease.
  • R 2 SnM SnBu 3
  • R 4 , R 5 C1, Br, Tosyl- ⁇ -, Nosyl- 0-, Tf-O-
  • the compound (1) of the present invention having a chelate-forming group can be obtained, for example, as follows.
  • the following reaction formula is a reaction formula for synthesizing the compound having ⁇ as a chelate-forming group.
  • reaction formula is a reaction formula for synthesizing the compound having the above-mentioned (F) as a chelate-forming group.
  • reaction formula is a reaction formula for synthesizing a compound having the above (D) and (E) as a chelate-forming group.
  • tert-butyl 2- (5— ⁇ [(6-amino-3-pyridyl) amino] carbol ⁇ — 2— Pyridyl) 1-hydrazinecarbochelate is obtained.
  • tert-butyl 2— (5— ⁇ [(6 amino 3 pyridyl) amino] carbol ⁇ 2 pyridyl) — 1 hydrazine carbochelate and 1— [4— (1 acetyl 1H— 3 pyrazolyl) phenyl ] 2-Promo 1 Ethanone is dissolved in dioxane and heated to reflux.
  • the chelate labeling method of the compound (1) of the present invention having a chelate-forming group is performed, for example, as follows.
  • sodium pertechnetate is used for Tc-99m labeling reactions. It can be carried out by a method of reacting a mixed solution with a ligand compound as a raw material in the presence of a reducing agent.
  • a Tc-99m labeled product can be obtained by performing a ligand exchange reaction on the technetium intermediate compound, which is also reduced in the raw material sodium pertechnetate. Examples of labeling schemes by each method are shown in the following formulas.
  • the compound (1) of the present invention has a property of passing through the blood-brain barrier and entering the brain, and has a strong binding affinity for amyloid aggregates or deposits. Furthermore, since it has high metabolic stability and no metabolite is present in the brain, it is useful as a compound for specific imaging of amyloid aggregates and deposits in the brain. That is, the compound (1) of the present invention is useful as an imaging agent, particularly as an amyloid imaging agent. Therefore, the use of the labeled compound of the compound (1) of the present invention enables imaging diagnosis of diseases caused by aggregation and Z or deposition of amyloid, such as amyloidosis, such as Aruno, Imah's disease, Down's syndrome, Kreuzfeld.
  • Jacob's disease type 2 diabetes, dialysis amyloidosis, AA amyloidosis, Gerstman Streisler.Shinker syndrome, Max'Wells syndrome, localized atrial amyloidosis, medullary thyroid cancer, cutaneous amyloidosis, localized sexual nodular amyloidosis, AL amyloidosis, AH amyloidosis, familial amyloid poly-eurobachi, senile systemic amyloidosis, cerebrovascular amyloidosis, familial Mediterranean fever, Parkinson's disease, tau This makes it possible to make an early diagnosis of opac, ALS or CAG repeat disease.
  • amyloidosis such as Alzheimer's disease, Down's syndrome, Creutzfeldt's Jacob Disease, type II diabetes, dialysis amyloidosis, AA amyloidosis, Gerstman's Streisler ⁇ -Shineker syndrome, Max'Welz syndrome, focal atrial amyloid, medullary thyroid cancer, cutaneous amyloidosis, localized Sex Nodular amyloidosis, AL amyloidosis, Sputum amyloidosis, Familial amyloid poly-Eurobati, Senile systemic amyloidosis, Cerebrovascular amyloidosis, Familial Mediterranean fever, Parkinson's disease, Tawapati, It is useful as a preventive and acupuncture or therapeutic agent for ALS or CAG repeat disease. Furthermore, it is useful as a screening tool
  • the compound (1) of the present invention when used as a diagnostic agent, it can be administered intravenously, intraarterially, intrathecally, etc., which may be local or systemic, and is suitable for the intended use and target disease Select the shape. Administer a detectable amount of the labeled compound of compound (1), allow sufficient time for the labeled compound to bind to the amyloid deposit (for example, 30 minutes at 48 hours), and label the labeled compound that has bound to the amyloid deposit. By detecting the compound, an amyloid deposit can be imaged.
  • the labeled complex combined with the amyloid deposit is detected by an imaging device (MRSZMRI, SPECT, Brunar scintillation image, PET, etc.) suitable for detection according to the target disease.
  • the diagnostic protocol depends on the disease, patient, and conditions appropriate for the detection device.
  • non-aqueous solvents at the time of administration are propylene glycol, vegetable oils, and injectable organic esters.
  • examples of the aqueous solvent include water, an alcohol solution, and physiological saline.
  • the compound (1) of the present invention when used as a medicament, it can be administered orally or parenterally, and a dosage form suitable for the intended use and the target disease may be selected.
  • Oral dosage forms include tablets, pills, capsules, powders, liquids for internal use, and parenteral dosage forms include injections, eye drops, suppositories, and suspensions. Suspending agents, ointments, poultices, liniments, lotions, aerosols, plasters, etc. it can. Formulation into these dosage forms is within a range not impairing the effect of the compound (1) of the present invention.
  • Excipients Excipients, binders, disintegrants, fluidizing agents, suspending agents, humectants, solubilizing agents, etc.
  • the dose of the compound (1) of the present invention may be appropriately determined depending on the type and extent of the disease, the administration method, the compound to be administered, and the age, sex and body weight of the patient.
  • the timing of administration include before meals, between meals, after meals, and before going to bed. Administration may be divided into 1 to several times.
  • the compound (1) of the present invention labeled with a radiation-emitting nuclide it may be appropriately determined in consideration of the measurement conditions of a radiation imaging apparatus such as a SPECT or PET apparatus and the exposure of the patient.
  • the radioactivity is 37 to 37 GBq, preferably l l l to 740 MBq.
  • the binding property between the subject and amyloid in vitro or in vivo. May be detected using the compound (1) of the present invention.
  • a method of detecting the binding between a specimen and amyloid using the compound (1) of the present invention after contacting the specimen with amyloid for example, amyloid ⁇ aggregate
  • the compound (1) of the present invention is used to measure the degree of amyloid aggregation and Z or deposition.
  • the degree of amyloid aggregation and Z or deposition using the compound (1) of the present invention can be measured.
  • the subject If it is found that the subject inhibits binding to amyloid or the like by using the compound (1) of the present invention, the subject can prevent and prevent amyloid-related diseases (amyloid cis) caused by amyloid protein. It turns out that it is useful as Z or a therapeutic agent.
  • amyloid-related diseases amyloid cis
  • Example 5 3 “4— (6—Yodomidazo“ 1.2 alpyridine-2 ”) ⁇ 1.2.4—Oxazia Zonole (17)
  • Example 8 5 “4— (6-Iodoimidazo” 1.2 Pyrimidine-2-yl) phenyl ⁇ 1. 3-Oxazole (25)
  • Example 2 The same procedure as in Example 1 was performed using 4- (6-bromoimidazo [1,2-a] pyridine-2-yl) benzaldehyde (255 mg) and p-toluenesulfol methylisocyanide (198 mg). The title compound (227 mg) was obtained.
  • Potassium hydroxide 39.6 g was dissolved in water (80 mL) at 0 ° C., and 2 amino-6 bromobenzothiazole (6.87 g) was added thereto and heated to reflux. After returning to room temperature, neutralized with 5N acetic acid aqueous solution and precipitated crystals were collected by filtration. The crystals collected by filtration are washed with water and depressurized. After drying by heating, the title compound (3.87 g) was obtained by recrystallization from isopropyl ether.
  • the target product When analyzed by TLC using a reverse phase silica gel plate (Whatman, KC18F) with 95% aqueous methanol as a developing solvent, the target product has an Rf value of about 0.5 and a radiochemical purity of 95% or more. Was about 2000 CiZm M.
  • Example 22 [4— (1H— 3 Pyrazoyl) phenol] — 6— (1, 1, 1-Tributylstarl) imidazole [1, 2-a] pyridine (triptylstar precursor)
  • 6 (1, 1, 1-Tributylstarl) imidazole [1, 2-a] pyridine (triptylstar precursor)
  • the same operation as in Example 22 was performed, and after adding an appropriate amount of ethanol and 50 mM ascorbic acid aqueous solution to a composition of about 1 to 2 mCiZmL of 5.
  • the solution was filtered through a 20 m membrane filter to prepare a target solution. Stored at –20 ° C for up to 8 weeks for in vitro binding and rat biodistribution experiments.
  • the Rf value of the target product is about 0.5, and the radiochemical purity is over 95%.
  • the specific activity was about 2000 CiZmmol.
  • the Rf value of the target product is approximately 0.5, and the radiochemical properties immediately after preparation and after 3 hours at room temperature. Both purities were over 90%.
  • tert-butyl 4- (4 acetylphenyl) -1H-1 pyrazole carboxylate (390 mg) and triethylamine (393 L) were dissolved in dichloromethane (10 mL), and bromotrimethylsilane ( 374 L) was added and stirred in argon gas at room temperature for 14 hours.
  • the reaction solution was washed with water and saturated brine, and dried over magnesium sulfate.
  • the brown oil obtained by distilling off the solvent under reduced pressure was dissolved in tetrahydrofuran (10 mL). N-Promosuccinimide (253 mg) was added thereto, and the mixture was stirred at room temperature for 1 hour.
  • tertbutyl 3- [4 (5-bromo-1,3benzoxazole-2-yl) phenyl] -1H-1-pyrazolecarboxylate (170 mg) was dissolved in 1,4 dioxane (5 mL).
  • Bistributyltin (303 ⁇ L) and tetrakistriphenylphosphine palladium (catalytic amount) were added, and the mixture was heated to reflux for 6 hours in an argon gas atmosphere.
  • the residue obtained by concentrating the reaction solution under reduced pressure was subjected to flash chromatography, and the fraction obtained from the eluate of dichloromethane was concentrated under reduced pressure to obtain a pale yellow oil.
  • the obtained brown solid was subjected to NH silica gel force ram chromatography, and the fraction obtained from the dichloromethane eluate was concentrated under reduced pressure and collected by filtration with isopropyl ether to obtain 1 [4- (6-bromo-1, 3 Benzoxazolu 2 yl) phenyl] -1 ethanone (586 mg) was obtained.
  • N-hydroxy-4- (5 bromo-1,3 benzoxazol-2-yl) benzamidine (266 mg) was suspended in triethyl orthoformate (3 mL) and heated to reflux for 24 hours.
  • the solid obtained by concentrating the reaction mixture was collected by filtration with isopropyl ether and dried under reduced pressure to give 5 bromo 2- [4- (1, 2, 4-oxazodiazol 3-yl) phenol] — 1,3 benzoxazole (190 mg) was obtained.
  • the reaction mixture was washed with aqueous sodium thiosulfate solution, water and saturated brine, and dried over magnesium sulfate.
  • the solid obtained by distilling off the solvent under reduced pressure was dissolved in methanol (2 mL), 3N hydrochloric acid (500 L) was added, and the mixture was stirred at room temperature.
  • a 3N sodium hydroxide aqueous solution 600 L was added to the reaction solution, extracted with chloroform, washed with water and saturated brine, and dried over magnesium sulfate.
  • the solid obtained by distilling off the solvent under reduced pressure was collected by filtration with isopropyl ether and dried under reduced pressure to obtain the title compound (46 mg).
  • the reaction mixture was diluted with ethyl acetate and filtered through celite, and the filtrate was concentrated under reduced pressure.
  • the reaction mixture was washed with aqueous sodium thiosulfate solution, water and saturated brine, and dried over magnesium sulfate.
  • the solid obtained by evaporating the solvent under reduced pressure was dissolved in methanol (2 mL), 3N hydrochloric acid (500 L) was added, and the mixture was stirred overnight at room temperature.
  • a 3N aqueous solution of sodium hydroxide (lmL) was added to the reaction mixture, extracted with chloroform, washed with water and saturated brine, and dried over magnesium sulfate.
  • the solid obtained by distilling off the solvent under reduced pressure was collected by filtration with jetyl ether, and dried under reduced pressure to obtain the title compound (34 mg).
  • the reaction mixture was concentrated under reduced pressure, extracted with ethyl acetate, washed with water and saturated brine, and dried over sodium sulfate.
  • reaction solution is diluted with ethyl acetate and filtered through Celite, and the residue obtained by concentrating the filtrate under reduced pressure is subjected to flash chromatography.
  • ⁇ hexane: ethyl acetate 1: 1 5 ⁇ ⁇ 4 [6— (1, 1, 1 tributylstanl) 3 ⁇ -imidazo [4, 5—b] pyridine-2-yl] phenol ⁇ — 1, 3 Oxazole (17 mg) was obtained.
  • 4-imidazo [1,2a] pyridine-2-ylbenzaldehyde (2.67 g) was dissolved in tetrahydrofuran (lOOmL) and stirred in ice-cooling.
  • methylmagnesium bromide (3.0 M jetyl ether solution, 4.4 mL) was added dropwise and stirred at room temperature for 1 hour.
  • a saturated aqueous solution of ammonium chloride (5 mL) was added dropwise to the reaction solution, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, extracted with black mouth form, and dried over magnesium sulfate.
  • the compound number indicates the Example number (for example, the compound of Example 3 is indicated as Compound 3).
  • Lipid solubility is the weight that affects the contrast of images obtained with radiolabeled derivatives.
  • the key factor The fat solubility (log D) at pH 7.4 was measured according to a method using high performance liquid chromatography (HPLC) equipped with a reverse phase column. At this time, a compound having a known log D shown in Table 1 was used as a fat-soluble standard substance, and the log D of the compound of the present invention was calculated by comparing with the fat-soluble standard substance.
  • the inventive compound was made into a 20 mol / L solution with 60% methanol to prepare a sample solution. Similarly, a 20 molZL standard solution was prepared for the fat-soluble standard substance.
  • HPLC HPLC was performed using a separation module Alliance2 690 connected to a 2487 Dual UV detector at a detection wavelength of 256 or 300 nM. Data analysis was performed using Millennium 32 (all manufactured by Waters Corporation). The column used Symmetry C18, 3.9 X 150 mm (manufactured by Waters Corporation), and the analysis was performed under the condition that the mobile phase flow rate was 1. OmL Z min. The mobile phase used was 20 mM 4 morpholine-propane sulfonic acid (MOPS) buffer (pH 7.4) and methanol concentration ranging from 40:60 to 15:85. The retention time of the standard solution and the sample solution was calculated by the following formula as a ratio.
  • MOPS morpholine-propane sulfonic acid
  • the capacity factor (k ′) at each methanol concentration was calculated as follows.
  • the log D value was calculated from the log kw (actual value) of the test substance using the relational expression between kw (actual value) and (document value).
  • Figure 1 shows the correlation equation between log kw and log D of the obtained fat-soluble reference material.
  • Table 2 shows the fat-solubility of the compounds of the present invention for which the correlation force of FIG.
  • the compound of the present invention is a group of compounds having an optimum fat solubility for passing through the blood-brain barrier and suitable for imaging.
  • [0217] [Table 1] Fat-soluble reference materials and literature values for their fat-solubility
  • Test Example 2 Binding to amyloid ⁇ -protein aggregates. Harmful experiment
  • Amyloid j8 (1-40) peptide 'hydrochloride (manufactured by Peptide Laboratories) was dissolved in purified water to a concentration of 200 ⁇ mol ZL. To this solution, add an equal volume of phosphate buffered saline solution (PBS (—)) prepared at a double concentration, and after sonication, gently agitate at 37 ° C for 4 days to synthesize synthetic amyloid 0 (1 —40) Aggregates were produced.
  • PBS (—) phosphate buffered saline solution
  • 500 / z L PBS, lOO ⁇ LOO. 2% BSA / PBS solution was added to a test tube.
  • the activity value is graphPad Prism Ver. 4.00 (Grad) when the concentration at which only ascorbic acid solution is added is taken as 100%, and the concentration that can inhibit up to 50% is IC.
  • Compound 23 is closer to the structure of Thioflavin T than Congo Red and FDDNP, and is strongly inhibited by IMPY and PIB. Therefore, it is considered that Compound 23 is a binding site similar to these compounds.
  • the compounds of the present invention inhibit binding more strongly than known compounds such as sputum and sputum, which are known to have binding activity to ⁇ -amyloid constituting senile plaques of Alzheimer's disease, and have stronger binding activity. It was shown to have.
  • Amyloid (1-40) peptide 'hydrochloride manufactured by Peptide Laboratories 15 ⁇ molZL and test substances 1.6, 8, and 40 111017 were incubated in 1 3 83 (—) at room temperature for 1 day. Thereafter, the amount of amyloid formation was measured by the thioflavin T method. The measured value was converted to a relative value (%) with respect to the amount of amyloid formation in the non-drug-added group, and then the 50% inhibitory concentration (IC 50 value) of amyloid liquid was calculated. Similarly, IC50 value was calculated by the same operation using amylin protein (Bacchem) molZL. The results are shown in Table 3. From this, it was shown that the compound of the present invention inhibits aggregation of amyloid ⁇ 8 (1-40).
  • I-IMPY amyloid ⁇ protein aggregate binding experiment was performed.
  • Synthetic amyloid (1-40) aggregates were prepared in the same manner as in Test Example 2, and 50 mg PBS was used.
  • a homogenate was prepared using a homogenizer with 5 times the amount of PBS as wet weight of brain tissue extracted from normal rats.
  • PBS in the presence of homogenate: 500 / z mL, absence: 600 L
  • 100 L of rat brain homogenate was added.
  • 100 L of ascorbic acid solution was added to 100 mL of 123 1-labeled substance having a concentration of 1.1 ⁇ CiZmL so that the reaction volume was 1 mL during the reaction.
  • 8 Aggregate 2-fold diluted series solution was added to the test tube 200 L at a time to start the reaction.
  • Nonspecific binding was determined by adding a solution obtained by diluting compound 1 to 5 ⁇ molZL with ascorbic acid solution in a test tube instead of adding 100 L of ascorbic acid solution (final concentration 500 nmolZL).
  • the SN (SignalZNoise) ratio was calculated by subtracting the nonspecific binding from the total binding and further dividing by the nonspecific binding to determine the relationship with the amyloid j8 protein aggregate (Fig. 2).
  • Both the 123 1-labeled compound 3 and 123 I-IMPY increased the amount of binding depending on the concentration of amyloid
  • the binding increased depending on the concentration of amyloid 8 protein aggregate, which was not affected by normal brain components.
  • the 1231- labeled compound 3 showed a higher SN value.
  • Test Example 5 Secondary structure analysis of amyloid ⁇ -white violent body
  • Circular dichroism (CD) measurement was performed on amyloid ⁇ 8 protein aggregates, and secondary structure analysis was performed.
  • Synthetic amyloid (1-40) aggregates were prepared in the same manner as in Test Example 2, and diluted with PBS to a concentration of 50 Onmol ZL. Furthermore, amyloid (1-40) peptide 'HC1 salt was dissolved in purified water to prepare a 100 / z molZL amyloid (1-40) solution. For CD spectral measurement, each solution was diluted 2 times, and the measurement wavelength ranged from 190 to 250 nm at room temperature (about 25 ° C). Blank measurement was performed on PBS or purified water. After the measurement, baseline correction was performed by subtracting the blank value from the CD value of each sample. Furthermore, obtained Secondary structure analysis was performed using the CD correction value of each sample. SELC ON3 was used for secondary structure analysis.
  • 8 (1-40) peptide solution are shown in FIG.
  • the obtained CD spectrum was analyzed for secondary structure using analysis software SELCON3 (Table 4). From the results of these secondary structure analyses, it became clear that the ⁇ -sheet structure increases as the aggregation reaction proceeds in PBS.
  • Binding to peptides was measured.
  • the experimental method was the same as in Test Example 3.
  • the label used in the reaction is Compound 24, which is a 1251 label, and does not include rat brain homogenate.
  • Each amyloid ⁇ concentration used was 50 nmol ZL during the reaction.
  • 8 (1-40) aggregate suspension prepared in PBS using compound 24 was bound to amyloid dissolved in purified water) 8 (1-40) solution The specific binding was increased approximately 20 times compared to the case of the treatment. From this, it is considered that compound 24 binds to amyloid b aggregates rich in sheet structure.
  • PBS aggregates and MES aggregates become 3: 1, 1: 1, 1: 3 (the ratio of PBS aggregates is 75, 50, and 25%, respectively). And further diluted with PBS to 40 / z molZL. Furthermore, PBS aggregates and MES aggregates were each diluted to 40 ⁇ mol ZL with PBS.
  • Thioflavin T method / 3 sheet volume of the aggregate is 96-well black half area well plate (manufactured by NUNC), 40 ⁇ mol / L aggregate solution 48. 75 ⁇ L and 2 mmol ZL thioflavin-T solution 1 25 L was added, and the fluorescence intensity at a wavelength of 490 nm at an excitation wavelength of 443 nm was measured with a microplate reader (MOLECULAR DEVICES).
  • the amount of compound 23 bound to the mixed aggregate obtained by mixing the aggregates prepared in PBS and MES was measured using the same method as the binding experiment for amyloid in Test Example 5.
  • the specific binding amount and non-specific binding amount of Compound 23 to the mixed aggregate, and the fluorescence intensity of the mixed aggregate are shown in FIG.
  • the fluorescence intensity of the mixed aggregates increased with the increase in PBS aggregates, which are enriched in
  • Test Example 7 Output of binding affinity using Alzheimer's disease brain
  • Binding experiment method The same procedure as in Test Example 2 was performed. Test compounds, using 200mmolZL Asukorubin acid ZPBS solution containing 20% ethanol, to produce a 4-fold dilution series to consist 0. 00019NM to 200nM in the reaction tube, 125 1-labeled test compound, the reaction test The solution was diluted with ascorbic acid solution to 0.5 nmol ZL in the tube. The reaction was started by adding the Algnoima disease brain homogenate diluted with PBS to all test tubes. Nonspecific binding was counted when the same operation was performed with Compound 1 added to 200 nmolZL in a reaction tube.
  • test substance and structure of the test substance is 125 1-labeled are the same, because it is thought to bind in exactly the same manner Ami port id clumps, and conversion calculated as all the test substances 125 1-labeled test substance, count data Were corrected and analyzed with GraphPad Prism Ver. 4.00 (GraphPad Software, Inc.) to calculate binding parameters (Kd, Bmax). The results are shown in Table 6.
  • Test Example 8 In vitro specific binding experiment using Alzheimer's disease brain
  • Binding experiment method 125 ⁇ -labeled test compound was diluted with the aforementioned ascorbic acid solution, and added to the reaction test tube so as to be 0.5 nmol / L. Furthermore, the total protein derived from Alzheimer's diseased tissue diluted with PBS was added in a test tube to a concentration of 50 ⁇ g protein ZL. The reaction was started at room temperature for 10 minutes, and then aspirated in the same manner as in the above test method. The reaction was stopped by filtration. In addition, non-specific binding is observed at 200 nmo in a reaction tube. Compound 1 was added so that it might become 1ZL, and it was set as the amount of coupling
  • the compound of the present invention has a higher binding rate and a higher binding rate than the known compound 125 I-IMPY, specifically binding to Alzheimer's disease brain under short-time incubation conditions. This is a suitable property for radiopharmaceuticals that must be taken into the brain in a short time and quickly disappear when administered in vivo!
  • Compound 23, Compound 24, and [ 12 3 ⁇ 4-IMPY were prepared in a solution containing 40 mM ascorbic acid and 0.1% Tween 80 to 100 ⁇ Ci / 200 ⁇ L, respectively. Force was also administered. 2, 5, 10, 20, 40, 60, 120 minutes after administration, the rats were decapitated under halothane anesthesia, and the brain and blood were immediately removed. The brain was divided into two equal parts, and the weight of each was measured. The right brain was placed in a vial and measured with a gamma counter. As a percentage of the dose, the radioactivity of each tissue was calculated as% L D./g tissue weight divided by% 1. D. or tissue weight.
  • Table 7 shows changes in brain radioactivity over time. All derivatives show good uptake into the rat brain, followed by rapid clearance. In a normal brain without amyloid aggregates, this behavior is shown when radioligand bound to amyloid stays in the brain when administered to a patient with Algno-Imma, but in areas without amyloid deposition, Is rapidly cleared and shows a distribution image of amyloid with high contrast within a short time.
  • the compounds incorporated into the rat brain were analyzed.
  • a homogenate was prepared using a potter-type homogenizer with 40 mmol / L ascorbic acid-containing ⁇ S added in an amount of 4 times the mass.
  • Four times as much acetonitrile as the volume of the homogenate was added, and after slow protein filtration, the acetonitrile layer was developed with reversed-phase TLC (Whatman KC18F). TLC was contacted to the imaging plate, and the radioactivity was detected with BAS-1800 (Fuji Film Co., Ltd.).
  • the brain homogenate 2, 5, 40, 60, 120 minutes after administration was gradually proteinized with acetonitrile, and the extracted radioactive material was analyzed by thin layer chromatography (KC18F, Whatman).
  • Figure 5 shows the results of TLC analysis after extracting radioactive substances accumulated in the brain.
  • the compounds of the present invention show that metabolites cannot be confirmed in the brain and most of them remain unchanged.
  • 125 1-IMPY was found to have multiple metabolites in the brain, and the proportion of metabolites increased with the passage of time after administration.
  • Liver microsomes commercially available from In Vitro Technologies (Pooled human Liver Microsomes ⁇ Male CD1 mouse, Male Wister Rat) were used.
  • Compound 23, Compound 24, and [ 12 3 ⁇ 4-IMPY were prepared with Milli Q water to 11 CiZmL (5 nmol / L), respectively.
  • Preparation of reduced nicotinamide adenine dinucleotide phosphate (NADPH) production system lOOmM glucose 6-phosphate and lOnmolZL NADPH mixed solution is mixed with an equivalent amount of ⁇ molZL salt ⁇ magnesium to terminate dulcose 6-phosphate dehydrogenase. Concentration was 1 Oun itZmL and prepared at the time of use.
  • NADPH reduced nicotinamide adenine dinucleotide phosphate
  • Compound 24 has very low metabolic rate and extremely high metabolic stability. Therefore, it is considered that not only the influence of metabolism by animal species is particularly small, but also the change of metabolic enzymes due to age and disease has little effect on pharmacokinetics. In addition, high metabolic stability can minimize the effects of metabolic enzyme induction by administration of therapeutic agents. The above is consistent with the purpose of the compound of the present invention capable of monitoring an Alzheimer's therapeutic agent.

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Abstract

La présente invention concerne un diagnostic qui est spécifiquement lié à un agrégat ou à un dépôt d’amyloïde et permet ainsi la visualisation ou la quantification d'une maladie provoquée par l'agrégation et/ou le dépôt d’amyloïde. A savoir, la présente invention concerne un composé représenté par la formule générale (1) : formule générale (1) (1) dans laquelle X1 représente un groupe hétérocycle bicyclique éventuellement substitué ; X2 représente un atome d'hydrogène, un atome d'halogène ou un groupe formant un chélate ; le cycle possédant A représente un cycle benzène ou un cycle pyridine ; et le cycle possédant B représente un groupe hétérocycle aromatique à 5 chaînons éventuellement substitué qui est lié au cycle benzène ou au cycle pyridine dans la formule au niveau de l'atome de carbone ; un sel de celui-ci, un solvate de celui-ci, un complexe de métal de transition de celui-ci et des médicaments contenant celui-ci dans des buts diagnostiques, préventifs ou thérapeutiques.
PCT/JP2006/323955 2005-11-30 2006-11-30 Diagnostic et remede pour une maladie provoquee par l’aggregation et/ou le depot d’amyloide WO2007063946A1 (fr)

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JP2007548001A JP4738419B2 (ja) 2005-11-30 2006-11-30 アミロイドの凝集及び／又は沈着に起因する疾患の診断薬及び治療薬
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